This is a multifaceted program consisting of five projects designed to increase our understanding of the cellular and molecular features of multi le myeloma and its genesis and relationship to monoclonalgammopathy of undetermined significance (MUU S). Dr. Kyle (Project I) will determine the prevalence of MGUS in Olmsted County. He will also follow the survivors of the Southeastern Minnesota MGUS cohort and all subsequently diagnosed cases in this population to assess predictors of outcome. Dr. Lust (Project II) will investigate the role of IL-1 beta on the expression and function of adhesion molecules in myeloma. Human myeloma cell lines that differ with respect to IL-1beta expression will be utilized as a model to study IL-lbeta in SCID mice. He will investigate the effects of IL-1beta and IL-1beta inhibitors on adhesion molecule expression on patient myeloma cells and on the adhesion of patient myeloma cells to bone marrow stromal cells. Dr. Witzig (Project III) will characterize the clonally related B cells found in MGUS and myeloma and investigate their capacity to be differentiated to plasma cells. He will determineheparan sulfate proteoglycan expression and the role of fibroblastic growth factors (FGF) and FGF receptors in the proliferation and apoptosis of myeloma cells. Dr. Van Ness (Project IV) will focus on the relationship between genetic alterations and apoptosis in myeloma cells. He will use myeloma cell lines to examine the effects of genetic alterations in Ras, p53, Rb, and PTP1C (SHP-1) on cell proliferation, apoptotic signaling, and therapeutic response. He will determine how genetic alterations affect apoptosis in myeloma by determining how expression of Bcl-2, BclXl, bad, and bax are regulated to enhance or protect cells from apoptosis. He will also study how apoptosis is mediated by therapeutic agents such as steroids, cytokines, alkylating, and antimitotic agents in myeloma cells with different genetic alterations. Dr. Jelinek (Project V) will focus on IL-6 mediated growth control of myeloma cells. The importance of JAK/STAT and Ras/MAPK pathways will be studied. She will identify and characterize the genetic targets of IL-6 signal transduction pathway (s) in myeloma by utilizing differential display reverse transcription polymerase chain reaction and cDNA array analysis. Core A will centralize cell collection and provide pure preparations of myeloma cells for each project. Core B will play a key role in project design and will provide statistical analysis of individual project data. It will also provide a central resource for sharing an coordinating data between the projects. The major aim of this Program Project is to obtain a better understanding of the pathophysiology of the monoclonal gammopathies. We believe that these results will ultimately translate into improved and novel therapeutic strategies.